Lecture 2: Absorption and Distriution Flashcards
Review and Forward
•The toxicity of a substance depends on the dose.
•However, it is ultimately not the dose but the concentration of
a toxicant at the site of action (target organ or tissue) that
determines toxicity.
•The concentration of a chemical at the site of action is often
proportional to the dose, but the same dose of two or more
chemicals may lead to vastly different concentrations in a
particular target organ of toxicity depending on the
disposition of the chemical.
•Disposition of a chemical depends on absorption,
distribution, biotransformation (metabolism) and
excretion.
Absorption of small hydrophilic molecules
•Small hydrophilic molecules (<600 Da) can pass through aqueous pores (sieve tubes or aquaporin)
Types of Transport
- Passive Diffusion—no ATP required; gradient driven
a. Simple Diffusion—hydrophobic molecules passively
diffuse across the lipid domain of membranes. Rate of
transport proportional to the octanol/water partition
coefficient or logP.
b. Facilitated Diffusion—saturable carrier-mediated
transport (e.g. glucose transporter)
Simple diffusion of weak organic acids and bases
•The ionized form usually has low lipid solubility and does not
permeate readily through the lipid domain of a membrane.
•The non-ionized form of weak organic acids and bases is
more lipid soluble, resulting in diffusion across the lipid domain
of the membrane.
•The pH at which a weak organic acid or base is 50 % ionized
is its pKa or pKb.
pH and ionization
The degree of ionization of a chemical depends on its
pKa and on the pH of the solution, a relationship
described by the Henderson-Hasselbalch equation.
For acids: pKa – pH= log [non-ionized]/[ionized]
For bases: pKb – pH=log [ionized]/[non-ionized]
pH Effect: Acid/Base effect on absorption
- R-CO2H would be absorbed under acidic conditions (e.g. stomach).
- R-NH2 would be absorbed at neutral pH (e.g. intestine, nasal passage).
Compounds will accumulate in total
amount where there are more binding sites
Applicable for the blood-brain barrier; toxicants with high affinity for binding proteins (e.g. albumin, hemoglobin) less likely to cross barrier.
Freebasing
Freebasing has been done with baking soda (sodium bicarbonate) or ammonia (NH3) to increase absorption of cocaine (crack) via
nasal installation.
- Active Transport
a) chemicals are moved against an
electrochemical gradient;
b) the transport system is saturable;
c) requires the expenditure of energy.
Routes of Administration: 1. Oral (GI tract)
• GI tract can be viewed as a tube traversing the
body.
•Although the GI tract is in the body, its contents
can be considered exterior to most of the body’s
metabolism.
•Unless the toxicant is an irritant or has caustic
properties, poisons in the GI tract do not produce
systemic injury until absorbed.
•Absorption can occur anywhere in the GI tract
including the mouth and rectum.
•Initial metabolism can
occur in gastric cells.
GI Tract Absorption
•Weak acids and bases will be absorbed by simple diffusion to a greater extent in the part of the GI tract in which they exist in the most lipid-soluble (non-ionized) form.
•Highly hydrophilic substances may be absorbed through transporters (xenobiotics with
similar structures to endogenous substrates).
•Highly hydrophobic compounds may be absorbed into the lymphatic system via chylomicrons.
•The greatest level of absorption for most ingested substances occurs in the small intestine.
Polar versus nonpolar GI absorption
Polar substances that are absorbed:
1. -go to the liver via the portal vein.
2. -may undergo first-pass metabolism
or presystemic elimination in gastric
and/or the liver cells where xenobiotics
may be biotransformed.
3. -can be excreted into the bile without
entrance into the systemic circulation or
enter the systemic circulation.
-The liver and first-pass metabolism serve as
the first-defense towards most
xenobiotics. The liver is the organ with the
highest metabolic capacity for xenobiotics.
Polar versus Non-polar GI Absorption (lipophilic)
Lipophilic non-polar substances (e.g. polycyclic aromatic hydrocarbons) 1. Ride on the “coattails” of lipids via micelles and follow lipid absorption to the lymphatic system (via chylomicrons) to the lungs. 2. Non-polar substances may by-pass first-pass metabolism. e.g. PAH have selective toxicity in the lung, where they are metabolically activated.
Routes of Administration: 2. Inhalation (Lung)
Toxicants absorbed by the lung are:
1. Gases (e.g. carbon monoxide, nitrogen dioxide,
sulfur dioxide, phosgene)
2. Vapors or volatile liquids (e.g. benzene and carbon
tetrachloride)
3. Aerosols
Gases and Vapors
The absorption of inhaled gases and
vapors starts in the nasal cavity
which has:
1. Turbinates, which increase the surface area for increased absorption (bony projections in
the breathing passage of the nose improving smell).
2. Mucosa covered by a film of fluid.
3. The nose can act as a “scrubber” for water-soluble gases and highly reactive gases, partially protecting the lungs from potentially injurious insults (e.g. formaldehyde, SO2).
-Rats develop tumors in the nasal turbinates when exposed to formaldehyde.
Absorption of Gases
•Absorption of gases differs from intestinal
and percutaneous absorption of compounds because:
1. Ionized molecules are of very low volatility, so their ambient air concentration is insignificant.
2. Epithelial cells lining the alveoli (type I pneumocytes) are very thin and the capillaries are in close contact with the pneumocytes, so diffusion distance is very short.
3. Chemicals absorbed by the lungs are rapidly removed by the blood (3-4 seconds for blood to go through lung capillary network).
Area for diffusion of gas
- total area for diffusion of gases is LARGE in humans ~50-100m^2
- diffusion path length is very SMALL <1um
When gas is inhaled through the lungs…
• When a gas is inhaled into the lungs, gas molecules diffuse from the alveolar
space into the blood and then dissolve.
• The gas molecules partition between the air and blood during the absorptive
phase, and between blood and other tissues during the distributive phase.
•Note that inhalation by-passes first-pass metabolism.
the gas continues to dissolve…
• The gas continues to dissolve into the blood until the gas molecules in blood are in equilibrium with the gas molecules in the
alveolar space.
•Once equilibrium is reached, the gas may not have reached saturation with the blood.
• At equilibrium, the ratio of the concentration of chemical in the blood and chemical in the gas phase is constant. The solubility ratio is called the blood-to-gas partition coefficient.
